This Program applies a combination of biochemistry, cell biology, genetics and mouse models of human cancer with a unified goal of revealing key tumorigenic pathways. \The success of targeted therapeutics continues to reinforce the view that understanding the biology of the cancer cell is the key to treating this disease. Throughout its 35 year history, this Program has focused on translating lessons from DMA tumor viruses into an understanding of both normal cellular and tumor biology. This remains a focus of the Program; however, as the view has shifted from viral to cellular proteins, so is the emphasis evolving from the cancer cell to a broader consideration of the tumor as a tissue. This Program is composed of six highly integrated and mutually supporting Projects and four Cores. The Program is unified by several themes which run throughout its components. First is the conviction that DNA tumor viruses have been driven by evolution to target the minimal set of fundamental cellular networks that hold the keys to tumorigenic growth. By moving downstream from the viral proteins themselves to their closest cellular counterparts, many projects within the program strive to understand how alterations in c-Myc promote transformation in different cellular and tissue contexts. The Program is also unified in the study of a new class of RNA regulatory molecules, the microRNAs, that act as oncogenes. The Program also exploits these as experimental tools to study gene function. Finally, the Program is cast in the context of sophisticated cancer models that use engineered stem and progenitor cells to rapidly reconstitute organ systems with nearly any desired genetic alteration. The findings from this Program have the potential both to inform the effective application of current therapies and to identify proteins and networks that may become targets for the development of new therapeutic agents.